Proliferation of the smooth muscle cells of the blood vessel induces hypertrophy of the intima of the blood vessel and, from a long-term view point, it causes, arteriosclelerotic diseases such as myocardial infarction, cerebral infarction and the like. Moreover, from a short-term view point, it induces reobstruction of the blood vessel after treatments of percutaneous transluminal coronary angioplasty (PTCA), stent and/or aterectomy. In consideration of the present situation, the therapeutic effects of conventional medicines used therefor are thought of as within certain limits, because they are classified as agents of indirectly effective for curing the diseases induced by the promotion factors of hypertrophy of the interim, for example hyperlipidemia, hypertension and the like. Therefore, development of essentially effective medicines therefor have been eagerly expected.
Generally, it is known that proliferation of the smooth muscle cells is related to the influence of cyclic guanosine 3',5'-monophosphate (cGMP). In this connection, pharmaceutical preparations of nitro group-containing compound known as coronary vasodilators activate the enzymatic activity of guanylate cyclase, and accentuate the production of cGMP, and also inhibit the proliferation of the cells. However, the pharmaceutical preparations of nitro group-containing compound are scarecely used for treatment of arteriosclerotic diseases which need to be administered for a long period of time, because the effect of the pharmaceutical preparations of nitro group-containing compound can be sustained only for a quite short time, and when they are administered repeatedly, then the tolerance against said pharmaceutical preparations may be occurred. On the other hand, in recent years, there have been reported several pharmaceutical preparations which can increase the concentration of cGMP by inhibiting the enzymatic activity of the enzyme [i.e., cGMP-PDE (cGMP-phosphodiesterase)] for decomposition of cGMP. However, there have not been suggested the activity for inhibiting proliferation of the smooth muscle cells performed by pharmaceutical preparations. The guanine derivative which was reported recently in an academic conference (IBC's International Conference on RESTENOSIS, 1994, U. S. A.) is the only known compound having both effects for inhibiting the enzymatic activity of cGMP-PDE and for inhibiting proliferation of the smooth muscle cells.
In consideration of the present status of such pharmacotherapy, and referring to the fact that cGMP relates to proliferation of the smooth muscle cells of the blood vessel, the present inventors have made an extensive research work regarding pharmaceutical preparations having the activity for inhibiting proliferation of the smooth muscle cells of the blood vessel which acts directly to the cells thereof, and can be used as the essential agent for treating arteriosclerotic diseases.
As the results, the present inventors have found the fact that the objective compounds, having the activity for inhibiting proliferation of the smooth muscle cells of the blood vessel, are existed among benzimidazole derivatives having property for inhibiting the enzymatic activity of cGMP PDE, thus the present invention has been completed.
Related art references which disclose compounds having chemical structural formulas similar to those disclose in the present invention are JP-A-2-306916, U.S. Pat. No. 4,886,803, U.S. Pat. No. 4,551,421, JP-A-62-246546, JP-A-4-346974, JP-A-61-167952, U.S. Pat. No. 4,994,477, U.S. Pat. No. 5,098,924, EP-A1-0560407, EP-A1-0407217, JP-A-64-65551, JP-A-1-96645, and JP-A-7-133224, however, those references neither disclose nor suggest benzimidazole derivatives of the present invention, and do not touch on inhibition of the enzymatic activity of cGMP PDE at all which benzimidazole derivatives of the present invention possess.
Furthermore, references JP-A-5-222000, WO-A-93-07124, and WO-A-94-22855 disclose structural similar compounds having inhibition of the enzymatic activity of cGMP PDE, however, those references neither disclose nor suggest benzimidazole derivatives of the present invention.